Search

Background/Aims: Difficult-to-treat HCV populations include patients with prior non-response to P/R, cirrhosis at baseline, and non- CC IL28B genotypes. ALV, a cyclophilin inhibitor, is pan-genotypic and targets the host protein cyclophilin A. This study investigated ALV plus P/R in this difficult-to-treat group. Method(s): Prospective, double-blind, multinational, randomized, placebo controlled trial evaluating P/R alone or in combination with ALV- 600 mg QD, 800 mg QD, or 400 mg BID in patients who previously failed P/R. Non-detectable HCV RNA (<25 IU/mL) at Week 24 (VR24)was evaluated according to prior P/R failure classification, IL28B genotype and cirrhosis status. Groups were compared via Cochran-Mantel-Haenszel test adjusted for stratification variables. Result(s): A total of 461 patients were enrolled; 77% were Caucasian, mean HCV RNA of 6.3 log10 IU/mL, 30% G1a, 24% had compensated cirrhosis (n = 109), 51% were P/R prior non-responders (n = 237; null NR, n = 154 (65%); partial NR, n = 74 (31%)) and 79% (n = 365) had non-CC IL28B genotype. The Table 1 lists the percentage of patients who achieved VR24 by prior P/R response and randomized treatment group. All ALV doses produced higher VR24 compared to P/R when cirrhosis was present (ALV 56.5%-65.4% vs P/R 17.2%; p<0.05). VR24 rates among non-CC IL28B genotypes, when compared to P/R (30.3%), were significantly improved in ALV 600 mg QD (42.7%, p = 0.0354), ALV 800 mg QD (54.0%, p = 0.0002) and ALV 400 mg BID (69.7%, p<0.00001) treated subjects. Conclusion(s): In difficult-to-treat HCV patients, the addition of ALV to P/R significantly improved treatment responses at 24 weeks. ALV could be an efficacious new treatment option in this patient population. (Table presented) .

Background/Aims: Difficult-to-treat HCV populations include patients with prior non-response to P/R, cirrhosis at baseline, and non- CC IL28B genotypes. ALV, a cyclophilin inhibitor, is pan-genotypic and targets the host protein cyclophilin A. This study investigated ALV plus P/R in this difficult-to-treat group. Method(s): Prospective, double-blind, multinational, randomized, placebo controlled trial evaluating P/R alone or in combination with ALV- 600 mg QD, 800 mg QD, or 400 mg BID in patients who previously failed P/R. Non-detectable HCV RNA (<25 IU/mL) at Week 24 (VR24)was evaluated according to prior P/R failure classification, IL28B genotype and cirrhosis status. Groups were compared via Cochran-Mantel-Haenszel test adjusted for stratification variables. Result(s): A total of 461 patients were enrolled; 77% were Caucasian, mean HCV RNA of 6.3 log10 IU/mL, 30% G1a, 24% had compensated cirrhosis (n = 109), 51% were P/R prior non-responders (n = 237; null NR, n = 154 (65%); partial NR, n = 74 (31%)) and 79% (n = 365) had non-CC IL28B genotype. The Table 1 lists the percentage of patients who achieved VR24 by prior P/R response and randomized treatment group. All ALV doses produced higher VR24 compared to P/R when cirrhosis was present (ALV 56.5%-65.4% vs P/R 17.2%; p<0.05). VR24 rates among non-CC IL28B genotypes, when compared to P/R (30.3%), were significantly improved in ALV 600 mg QD (42.7%, p = 0.0354), ALV 800 mg QD (54.0%, p = 0.0002) and ALV 400 mg BID (69.7%, p<0.00001) treated subjects. Conclusion(s): In difficult-to-treat HCV patients, the addition of ALV to P/R significantly improved treatment responses at 24 weeks. ALV could be an efficacious new treatment option in this patient population. (Table presented) .

Background/aims: ALV suppresses HCV replication by inhibiting cyclophilin A, a host protein essential for HCV replication, with pangenotypic activity and high barrier to resistance. The FUNDAMENTAL study investigated viral response to combinations of oral ALV plus P/R in CHC G1 failing prior P/R treatment, including hardest-totreat populations: prior non-responders, cirrhotic at baseline, and IL28B CT/TT genotypes. Method(s): Prospective, double-blind, multinational, randomized, placebo controlled trial evaluating P/R alone or in combination with ALV 600 mg QD, 800 mg QD, or 400 mg BID in patients who previously failed P/R. Following a partial clinical hold imposed by FDA, ALV/placebo was discontinued in all patients; at that time, all active patients had received at least 31 weeks of triple therapy out of a total of 48 weeks. Patients randomized to ALV containing groups were allowed to complete the scheduled 48 weeks on P/R only. Nondetectable HCV RNA (<25 IU/mL) at Week 72 (SVR24) was evaluated according to pre-specified categories and a logistic regression (multivariate analysis) was conducted. Result(s): A total of 459 patients were randomized; 77 % were Caucasian, mean HCV RNA of 6.3 log10 IU/mL, 30 % G1a, 25 % had compensated cirrhosis/transition to cirrhosis, 57 % were P/R prior non-responders and 79 % had IL28B CT/TT genotype. All ALV dosing added to P/R significantly improved treatment responses in a dose-dependent fashion, with 400 mg BID achieving the best responses vs P/R: null non-response (67.6 vs 2.8 %); cirrhosis/transition to cirrhosis (52.2 vs 0 %), and IL28B CT/TT genotypes (65.2 vs 11.5 %). Most frequently reported AEs with ALV/PR were hematologic abnormalities, GI symptoms, hypertension, hyperbilirubinemia and hypertriglyceridemia; frequency was higher in the 400 mg BID arm. Conclusion(s): The addition of ALV to P/R significantly improved SVR24 in CHC G1 patients who previously failed P/R therapy. All doses of ALV were superior to P/R alone; 400